In vivo sensor and method of making same

ABSTRACT

Implantable in vivo sensors used to monitor physical, chemical or electrical parameters within a body. The in vivo sensors are integral with an implantable medical device and are responsive to externally or internally applied energy. Upon application of energy, the sensors undergo a phase change in at least part of the material of the device which is then detected external to the body by conventional techniques such as radiography, ultrasound imaging, magnetic resonance imaging, radio frequency imaging or the like. The in vivo sensors of the present invention may be employed to provide volumetric measurements, flow rate measurements, pressure measurements, electrical measurements, biochemical measurements, temperature, measurements, or measure the degree and type of deposits within the lumen of an endoluminal implant, such as a stent or other type of endoluminal conduit. The in vivo sensors may also be used therapeutically to modulate mechanical and/or physical properties of the endoluminal implant in response to the sensed or monitored parameter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of commonly assigned and co-pending U.S. patentapplication Ser. No. 15/257,885, filed Sep. 6, 2016; which is acontinuation U.S. patent application Ser. No. 13/596,923, filed Aug. 28,2012, now U.S. Pat. No. 9,433,515; which is a continuation of U.S.patent application Ser. No. 09/783,633, filed Feb. 14, 2001, now U.S.Pat. No. 8,372,139, which are hereby incorporated by reference in theirentirety.

BACKGROUND

The present invention relates generally to the field of implantablemedical devices, and more particularly pertains to sensors that may beimplanted into a body to elicit at least one of a mechanical, chemicalor electrical response to an in vivo physiological condition or statewith the body.

Post-implantation evaluation of the patency of an endoluminal devicepresently requires clinical examination by angiography or ultrasound.The results of these tests provide a qualitative evaluation of devicepatency. It is, therefore, desirable to provide a means forquantitatively measuring the post-implantation patency of an endoluminaldevice on either a periodic or continuous basis. Quantitative in vivomeasurements of volumetric flow rate, flow velocity, biochemicalconstitution, fluid pressure or similar physical or biochemical propertyof the body fluid through an endoluminal device would provide moreaccurate diagnostic information to the medical practitioner.

As used herein, the term “endoluminal device” is intended to includestents, grafts and stent-grafts which are implanted within an anatomicalpassageway or are implanted with a body to create a non-anatomicalpassageway between anatomically separated regions within the body.Endoluminal devices in accordance with the present invention may includeendovascular devices, prostatic devices, urethral devices, cervicaldevices, esophageal devices, intestinal devices, biliary devices,intra-cardiac devices, valves, hepatic devices, renal devices or deviceswith similar application within the body.

The term “sensor,” as used in this application, is intended to include,without limitation, biosensors, chemical sensors, electrical sensors andmechanical sensors. While the term “biosensor” has been used tovariously describe a number of different devices which are used tomonitor living systems or incorporating biological elements, theInternational Union for Pure and Applied Chemistry (IUPAC) hasrecommended that the term “biosensor” be used to describe “a device thatuses specific biochemical reactions mediated by isolated enzymes,immunosystems, tissues, organelles or whole cells to detect chemicalcompounds usually by electrical, thermal or optical signals” 1992, 64,148 IUPAC Compendium of Chemical Terminology 2nd Edition (1997). Theterm “chemical sensor” is defined by the IUPAC as a device thattransforms chemical information, ranging from concentration of aspecific sample component to total composition analysis, into ananalytically useful signal. Conventional biosensors are a type ofchemical sensor that consists of three basic elements: a receptor(biocomponent), transducer (physical component) and a separator(membrane or coating of some type). The receptor of a chemical sensorusually consists of a doped metal oxide or organic polymer capable ofspecifically interacting with the analyte or interacting to a greater orlesser extent when compared to other receptors. In the case of abiosensor the receptor or biocomponent converts the biochemical processor binding event into a measurable component. Biocomponents includebiological species such as: enzymes, antigens, antibodies, receptors,tissues, whole cells, cell organelles, bacteria and nucleic acids. Thetransducer or physical component converts the component into ameasurable signal, usually an electrical or optical signal. Physicalcomponents include: electrochemical devices, optical devices, acousticaldevices, and calorimetric devices as examples. The interface or membraneseparates the transducer from the chemical or biocomponent and linksthis component with the transducer. They are in intimate contact. Theinterface separator usually screens out unwanted materials, preventsfouling and protects the transducer. Types of interfaces include:polymer membranes, electropolymerized coatings and self-assemblingmonomers.

Sensors should have high selectivity and sensitivity, have rapidrecovery times with no hysteresis, long lifetimes if not single use, lowdrift, automated calibration, self-diagnostic, low cost, no reagentadditions required and no sample preparation. It is obvious thatpresently available chemical sensors and biosensors do not meet thesecriteria (World Biosensor Market, Frost and Sullivan, Report 5326-32,1997). National Institute of Standards and Technology, Nano- and MEMSTechnologies for Chemical Biosensors,(www.atp.nist.gov/atp/focus/98wp-nan.htm).

In the clinical diagnostic market, various sensor designs are knownincluding electrochemical sensors (potentiometric ISEs; amperometric;conductometric; miniaturized ISEs; field effect transistors;interdigitated transistors); optical sensors using fiber-optic orsurface plasmon resonance technologies; acoustic sensors such aspiezo-crystal and surface acoustic wave sensors; and thermal sensorswhich employ thermistors. Thus, it is known to employ microfabricationtechniques to make clinical sensors. Currently, the most commerciallysuccessful microfabricated sensor in the clinical diagnostic market isthe MEDISENSE glucose meter that uses an electrochemical transduction ofan enzymatic reaction. However, the need for in vivo sensing systems iswell recognized. Work on in vivo sensing systems for both glucose andlactate has confirmed the effectiveness of phospholipid copolymers inimproving hemocompatibility. Fisher, U., et al. Biosen. Bioelectron.,10, xxiii (1995).

By their nature, implantable sensors must have some mechanism forcommunicating sensed information from the sensor to a reader, which maybe human or machine, outside the body. Since it is impractical toimplant a physical connection between the sensor and the externalreader, alternative means for generating a readable signal external thebody must be provided. Suitable means for generating a readable signalexternal the body include, without limitation, radiographically visiblesignals, magnetic flux signals, chemical signals, chemifluorescentsignals, and/or electrical signals.

The pathogenesis of arteriosclerosis has not been positively identified.A number of risk factors, such as high cholesterol, hypertension, anddiabetes are known to serve to turn on inflammatory mechanisms at thearterial wall and recruit white cells into the arterial wall toultimately cause the formation and breakdown of plaque, which, in turn,lead to clinical events. The process starts out with oxidation-sensitivenuclear regulatory mechanisms. Free radicals control the genes thatcause the synthesis of proteins that are expressed in the endothelialcells and serve to attract white cells into the arterial wall.

Endothelialization of an implanted medical device has been the subjectof considerable scientific study and literature. It is known thatvarious growth factors and cytokines are responsible for activatingsmooth muscle cell receptors and initiating smooth muscle cellproliferation. Endothelial cell growth factors such as fibroblast growthfactor (FGF) and vascular endothelial growth factor (VEGF) have beenidentified as significant for endothelial cell growth in vitro. WhileVEGF is specific for endothelial cells, FGFs also stimulate smoothmuscle cell growth. Bauthers, C., Growth Factors as a Potential NewTreatment for Ischemic Heart Disease, Clin. Cardiol. 20:11-52-11-57(1997).

It has been recognized that there is a need for an in vivo sensorcapable of sensing binding of endothelial cells or arterioschleroticplaque, and providing an ex vivo detectable signal, without requiringexternal or internal power sources.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided animplantable in vivo sensor suitable for monitoring clinicallysignificant physiological events. The present invention provides anintegrated device which is implantable within an anatomical passageway,such as a blood vessel, in the esophageal or gastro-intestinal tract,bile duct, hepatic duct, within the renal system, such as within aureter or urethra, vagina or cervix, vas deferens, bronchi or similaranatomical passageways; within an organ, or within an anatomical defect,such as a cardiac septal defect.

The inventive in vivo sensor consists generally of an implantablesubstrate carrier element and at least one of a plurality of sensorelements. The implantable substrate carrier element may consist of, forexample, a stent, stent-graft, graft, valve, filter, occluder or otherimplantable medical device, which serves as a foundational element forthe sensor elements. Under conditions where the implantable substratecarrier, itself, is configured to return a detectable signal, theimplantable carrier element, itself, may constitute the sensor element.Where the implantable substrate carrier element and the sensor elementare discrete, conjoined elements, they may be fabricated of likematerials or of dissimilar materials, each having either similar ordissimilar thermal, mechanical, electrical and/or chemical properties.

Microfabrication techniques are preferably employed to create both thecarrier element and the sensor element in such a manner that both thesubstrate carrier element and the sensor element have a defined geometryand conformation that is suitable for use as a thermal, electrical,mechanical or chemical sensor, for sensing, for example, fluid flow,fluid flow rate, or fluid pressure in the region of the sensor. Theaddition of chemical or biological compounds to inventive sensor permitsthe device to be used as either a chemical or a biosensor, respectively.Similarly, microelectronic circuits may be added to the inventivesensor, such as by fabricating integrated circuits into or onto theinventive sensor, to enable the sensor to detect electrochemical eventsoccurring at the sensor, such as arteriosclerotic plaque being depositedonto the surface of the sensor, or to detect electrochemical changes inthe anatomical environment into which the sensor is implanted.

Alternatively, the inventive implantable sensor element and theimplantable substrate carrier element may be fabricated of wroughtmaterials, such as stainless steely hypotubes, stainless steel wire,shape memory hypotubes and shape memory wires. The sensor element may beattached to the substrate carrier element, or component parts, such ascantilever members, of the sensor element may be attached to the sensorelement by a variety of known means. For example, welding processes maybe used, such as laser welding, plasma welding, resistance welding, ore-beam welding. Welding, however, is generally not an acceptable methodfor joining nickel-titanium alloys to other materials, e.g., stainlesssteel, because brittle intermetallics may be formed in the weld zone. Inorder to obtain a weld that is free of oxides or nitrides, weldingshould be performed under stringent environmental conditions in a clean,inert atmosphere or in vacuum in order to minimize reactivity of thetitanium. In some cases, welded nickel-titanium parts may requireheat-treating after welding to stress relieve the weld zone. Theheat-affected zone will generally not exhibit superelastic properties.Soldering may be employed to join shape memory or superelastic alloys,such as nitinol, to stainless steel and other materials. However, aproper flux must be selected which inhibits the formation of surfaceoxides during the soldering process. Ultrasonic soldering has also beenused to try to keep the surface free of oxides during soldering. Variousepoxies and other adhesives may be used to join shape memory alloyseither to themselves or to other materials. The chosen adhesives must,of course, be compatible with both the manufacturing and in vivobiological environments of the device. Finally, the sensor element maybe mechanically joined to the substrate carrier element, or componentparts of the sensor element maybe joined together by crimping, providingan interference fit or by creating interlocking geometries of the sensorelement or its component parts.

In accordance with a particular embodiment of the present invention, anendoluminal implant is provided which is implantable within ananatomical or non-anatomical body passageway to determine a givencondition of a fluid flow through the endoluminal implant within thebody passage. The inventive endoluminal implant may include, forexample, an endoluminal stent, stent graft, or graft that consists of agenerally tubular shaped member having two diametric states. In order tofacilitate transluminal catheter introduction, the inventive endoluminaldevice has a first diametric state in which the transversecross-sectional area of the device is of sufficient size to permitpercutaneous introduction and in vivo placement of the device usingtransluminal approaches. A second diametric state has a transversecross-sectional area which is larger than the first diametric state andconforms to the diameter of the anatomical passageway into which thedevice is placed, or is of a desired diameter for non-anatomicalpassageways. The inventive endoluminal device may be fabricated as aballoon expandable device, a self-expanding device, a shape-memorydevice or a superelastic device. It will be understood by those of skillin the art that the term “balloon expandable” refers to a class ofdevices which rely upon application of an external pressure, such asthat applied by a balloon catheter, to radially deform the device fromits first diametric state to its second diametric state; that the term“self-expanding” refers to a class of devices which rely upon theinherent mechanical properties of the device material to expand thedevice from its first diametric state to its second diametric state;that the term “shape-memory” refers to a class of devices which arefabricated of materials which exhibit martensitic phase transformationat certain transition temperatures; and the term “superelastic” refersto a class of devices which are fabricated of materials which deformunder given stress-strain conditions. The inventive endoluminal sensormay be fabricated of materials capable of undergoing elastic or plasticdeformation, such as stainless steel, tantalum, titanium, gold, or otherbiocompatible metals. However, the present invention is preferablyfabricated of a shape-memory and/or superelastic material, such asnickel-titanium alloys known as Nitinol, which are mechanicallyresponsive to temperature changes and/or changes in applied stress orstrain, respectively.

Generally, the inventive endoluminal sensor consists of a sensor whichis integral with an implantable endoluminal device, such as stent, andwhich is configured to respond either mechanically, electronically,electromechanically, or chemically, to cause a mechanical, electrical,electromechanical or chemical change at the sensor and/or theendoluminal device which is detectable ex vivo using non-invasivedetection methodologies such as radiography, ultrasonography, magneticresonance imaging, or radio frequency detection.

In accordance with one embodiment of the invention, the inventive sensorcomprises at least one integral region of the implantable endoluminaldevice that is formed as a plurality of cantilever members fabricated ofshape-memory materials having different transformation temperatures. Thesensor may be positioned on either a fluid contacting ortissue-contacting surface of the implantable device, such as the luminalsurface of a stent which contacts blood, or on the abluminal surface ofa stent which contacts neointimal tissue of the blood vessel.Alternatively, the sensors may be positioned on both the fluidcontacting and the tissue-contacting surface of the implantable device.The present invention provides a vacuum deposited film which may beeither a monolithic monolayer of material or a multilayered film havingat least portions of the film capable of sensing at least one of changesin temperature, pressure, or the presence or absence of chemical orbiochemical species in the body by mechanical, electrical, chemical,electrochemical or electromechanical means.

Specifically, the present invention relates to the manufacture and useof implantable sensors to monitor physical, chemical or electricalparameters of a fluid flow through a body passageway. For example, thesensors of the present invention may be employed to provide volumetricmeasurements, flow rate measurements, pressure measurements, electricalmeasurements, biochemical measurements, temperature, measurements, ormeasure the degree and type of deposits within the lumen of anendoluminal implant, such as a stent or other type of endoluminalconduit. The present invention also provides a means to modulatemechanical and/or physical properties of the endoluminal implant inresponse to the sensed or monitored parameter. For example, where themonitored blood flow volume through an endoluminal device is determinedto be below physiological norms and/or the blood pressure is determinedto be above physiological norms, the stent may be actuated to increaseits diameter, such as by superelastic properties of the stent materials.

BRIEF DESCRIPTION OF THE DRAWINGS

In the accompanying figures, like elements are identified by likereference numerals among the several preferred embodiments of thepresent invention.

FIG. 1 is a perspective view of an endoluminal implant in accordancewith the present invention.

FIG. 2 is a cross-sectional view taken along line 2-2 of FIG. 1.

FIG. 3 is a fragmentary plan view of a first embodiment of the presentinvention illustrating an integral sensor formed of a plurality ofcantilever members.

FIG. 4 is a cross-sectional view taken along line 4-4 of FIG. 3.

FIG. 5 is a perspective view of an endoluminal implant in accordancewith a second embodiment of the present invention.

FIG. 6 is a fragmentary plan view of a diametrically adjustable regionof the second embodiment of the present invention.

FIG. 7A is a perspective view of the second embodiment of the inventiveendoluminal implant of the present invention in its diametricallyreduced state.

FIG. 7B is a perspective view of the second embodiment of the inventiveendoluminal implant of the present invention in its diametricallyexpanded state.

FIG. 8 is a perspective view of a third embodiment of the inventiveendoluminal implant of the present invention depicting weakened regionsin the bulk material in phantom.

FIG. 9 is a fragmentary enlarged plan view of circled region 9 in FIG.8.

FIG. 10 is a fragmentary plan view illustrating propagation of amicrogroove upon binding of an endothelial cell to a binding domain atthe weakened region in the bulk material of the third embodiment of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The foregoing and other features and advantages of the invention areapparent from the following detailed description of exemplaryembodiments, read in conjunction with the accompanying drawings. Thedetailed description and drawings are merely illustrative of theinvention rather than limiting, the scope of the invention being definedby the appended claims and equivalents thereof.

To simplify description of the present invention, most of the preferredembodiments will be described with reference to an endoluminal stent,except where otherwise stated. However, those of ordinary skill in theart will understand that each embodiment has application to a variety ofimplantable devices including, without limitation, stents, grafts,stent-grafts, valves, shunts or patches.

As used herein, the term “integral” is intended to include regions thatare formed as a part of the bulk material of the endoluminal device andregions which are formed separately from the bulk material of theendoluminal device, but which are coupled thereto.

In accordance with another embodiment of the invention, the inventivesensor comprises at least one region of the implantable endoluminaldevice that is formed of a plurality of cantilever members havingdifferent mechanical properties, such as different modulus ofelasticity, plasticity or stress-strain behaviors. In accordance withthe best mode presently contemplated for the invention, the cantilevermembers are preferably fabricated of a superelastic material. As withthe shape-memory cantilever members, the superelastic cantilever membersmay be positioned on either a fluid contacting or tissue contactingsurface of the implantable device, such as the luminal surface of astent which contacts blood, or on the abluminal surface of a stent whichcontacts neointimal tissue of the blood vessel. Alternatively, thesensors may be positioned on both the fluid contacting and thetissue-contacting surface of the implantable device. Unlike theshape-memory cantilever sensors, the superelastic cantilever sensors areresponsive to changes in force, such as shear forces, applied to thesensors.

With both the shape-memory cantilever members sensor and thesuperelastic cantilever members sensor, each of the plurality ofcantilever members have first and second positions that are indicativeof either an off or on position, respectively. The first or “off”position of each cantilever members is coplanar or flush with thesurface of the endoluminal device into which the sensor is positioned.In the second or “on” position, each activated cantilever membersprojects outwardly from the surface of the endoluminal device into whichthe sensor is positioned. Because different cantilever members or groupsof cantilever members are fabricated to have either different transitiontemperatures or different stress-strain properties, individualcantilever members or groups of cantilever members which are in thesecond or “on” position, are indicative of a given thermal orstress-strain condition existing within the body into which theendoluminal device is implanted.

In one particular form of the invention, the inventive endoluminaldevice comprises a temperature sensor having a plurality of cantilevermembers positioned on at least one of the proximal, distal orintermediate regions of the endoluminal device and positioned on atleast one of the luminal or abluminal wall surfaces of the endoluminaldevice. To facilitate ease of detection, a plurality of groups ofcantilever members are provided, each group is formed of a plurality ofindividual cantilever members, with each individual cantilever membersin the group having identical transition temperatures. The plurality ofgroups of cantilever members are arrayed along the longitudinal axis ofthe endoluminal device in such a manner as to create a continuum ofgroups of cantilever members having different transition temperatures.Changes in temperature at the site of the endoluminal device areindicated by the position of the cantilever members or groups ofcantilever members as determined by radiography, ultrasonography,magnetic resonance imaging or other means that provides a detectableimage of the position of the cantilever members and groups of cantilevermembers.

In another particular form the invention, the sensor comprises aplurality of cantilever members positioned on at least one of theproximal, distal or intermediate regions of the endoluminal device andpositioned on at least one of the luminal or abluminal wall surfaces ofthe endoluminal device. To facilitate ease of detection, a plurality ofgroups of cantilever members are provided, each group is formed of aplurality of individual cantilever members, with each individualcantilever members in the group having identical transitiontemperatures. The plurality of groups of cantilever members are arrayedalong the longitudinal axis of the endoluminal device in such a manneras to create a continuum of groups of cantilever members havingdifferent stress-strain transition pressures. Changes in applied stressor strain, such as blood pressure or blood flow shear stress, at thesite of the endoluminal device are indicated by the stress and strainacting on the cantilever members or groups of cantilever members whichprovides a corresponding frequency shift in energy reflected, whencompared to a baseline stress-strain for unloaded cantilever members.The position and frequency shift of the cantilever members may bedetermined by radiography, ultrasonography, magnetic resonance imagingor other means which provides a detectable image of the position of theindividual cantilever members and groups of cantilever members or iscapable of measuring frequency shifts due to differential stress-strainloading onto the cantilever members.

In yet another form of the invention, the inventive sensor is abiosensor that is microfabricated from a material capable of undergoingelastic, plastic, shape-memory or superelastic deformation, and has aplurality of cantilever members formed therein, as described above. Eachof the plurality of cantilever members has at least one binding domainselective for at least one indicator of endothelialization selected fromthe group of endothelial cell surface proteins, antigens, antibodies,cytokines, growth factors, co-factors, or other biological orbiochemical marker of endothelial cells or endothelial cell precursors.Binding of the at least one indicator to at least one of the pluralityof cantilever members causes a change in strain applied to thecantilever members, thereby causing the relevant cantilever members orgroups of cantilever members to undergo superelastic transformation fromthe first or “off” position to the second or “on” position. As with theabove-described embodiments of the invention, the position of the sensorcantilever members in the second or “on” position relative to theendoluminal device is then detected and is indicative of the progress ofendothelialization.

Similarly, the fact of or the progress of arterioschlerotic plaqueformation may be sensed using a plurality of elastic or superelasticcantilever members. In accordance with a first embodiment, the pluralityof superelastic cantilever members undergo martensitic transformation asa result of the strain applied to the cantilever members resulting fromgrowth of arterioschlerotic plaque onto the cantilever members. Inaccordance with a second embodiment, the plurality of superelasticcantilever members has at least one binding domain selective for atleast one indicator of arterioschlerotic plaque or its precursors.Binding of the arterioschlerotic plaque or precursors ofarterioschlerotic plaque to the binding domain on the cantilevermembers, adds a quantum of strain to the cantilever members sufficientto cause the cantilever members to undergo superelastic transformationfrom the first or “off” position to the second or “on” position. As withthe above-described embodiments of the invention, the position of thesensor cantilever members in the second or “on” position relative to theendoluminal device is then detected and is indicative of the progress ofarteriosclerosis.

Yet another form of the invention entails an implant fabricated of asuperelastic material that has a variable diametric geometry responsiveto changes in pressure applied to the implant. This form of theinvention is preferably employed as a smooth muscle prosthesis, forexample, as a vascular prosthesis, and is responsive to blood pressurechanges in a manner similar to those changes native to blood vessels,i.e., contracting upon sensing lowered blood pressures and expandingupon sensing higher blood pressures, in order to maintainphysiologically normal blood pressure. In this embodiment of theinvention, a tubular implant is fabricated, in whole or in part, of asuperelastic material and has diametrically adjustable regions thatundergo superelastic transformation to increase or decrease the diameterof the implant upon sensing given physiological pressures within theimplant.

Finally, another form of the invention consists of an endoluminalimplant similar to that described in co-pending, commonly assigned U.S.Patent Application Ser. No. 60/064,916, filed Nov. 7, 1997 which waspublished as PCT International Application WO9923977A1 entitledIntravascular Stent And Method For Manufacturing An Intravascular Stent,both of which are hereby incorporated by reference. In thoseapplications there is described an endoluminal implant having aplurality of microgrooves on the luminal and/or abluminal surfacesthereof which facilitate improved endothelialization over a non-groovedendoluminal implant. In accordance with the present invention there isprovided an endoluminal implant having a plurality of putativemicrogrooves comprising sections of weakened bulk material of theendoluminal implant. The endoluminal implant is preferably fabricated ofa superelastic bulk material and weakened regions in the bulk materialare formed using standard microlithographic techniques to form theputative microgrooves. A plurality of binding domains are created alongthe fluid flow surface of the endoluminal implant and at proximal(relative to the blood flow) regions of the putative microgrooves thatpreferentially bind to endothelial cell surface proteins. Binding of theendothelial cell surface proteins to the binding domains causes a shiftin the applied strain to the superelastic bulk material, which causesthe superelastic bulk material to deform in the region of the appliedstrain, thereby breaking the interatomic bonds in the weakened regionsof the putative microgrooves and causing formation of a portion of amicrogroove. Propagation of the endothelial cell proliferation along thesurface of the superelastic bulk material causes, in turn, a propagationof strain along the superelastic bulk material that causes the formationof the microgrooves in the superelastic bulk material.

The particular means for detecting a change in the inventive sensorand/or the particular means for activating a change in the inventivesensor is generally not considered part of the present invention. Forexample, it is known that ultrasound energy may be employed to generateboth one-way and two-way shape memory effects in nickel-titanium alloys.V. V. Klubovich, V. V. Rubanick, V. G. Dorodeiko, V. A. Likhachov, andV. V. Rubanick Jr. (Institute of Tech. Acoustics, 13 Ludnikova, 210026Vitebsk, Belarus,) Generation of Shape Memory Effect in Ti—Ni Alloy bymeans for Ultrasound, Abstract 1.P12, SMST-97 conference found at URLhttp://www.fwsystems.com/professional/smstabs.html. Using ultrasoundenergy to non-invasively induce stent heating has also been confirmed byB. Lal, et al. in their abstract entitled Non-Invasive UltrasoundInduced Heating of Stents: Importance of Stent Composition, which may befound at URL http://www.hotplaque.com/frames/abstracts/rabs6.htm and URLhttp://ex2.excerptamedica.com/00acc/abstracts/abs1065-117.html. Lal, etal. hypothesized that gentle heating can be accomplished usingultrasound (US) and a constant temperature can be maintained usingpulsed US. The heating rate of an object under the same US power andfrequency is determined primarily by its absorption and reflectionrates. To test their hypothesis, they used a phantom of 5.08 cm thicklayer of pork muscle, in which various annular stent shape materialswere placed. To monitor the heating multiple hypodermic thermocoupleswere used. The heating was induced using FDA-approved levels oftherapeutic ultrasound (intensity 0.5-2.5 W/cm.sup.2, frequency 1-3 MHz)in both pulse and continuous modes. It was found that nylon, and sometypes of PVC, exhibit temperature increases that are larger (2-35° C.)and faster (1.5-15 times) than the surrounding tissue, while Lexan,PTFE, Latex, Teflon, Ceramic and Delrina do not display selectiveheating. A modest heating effect (2° C. increase in 15 minutes) was alsofound in a metal stent. Lal, et al. concluded that ultrasound heating oftissue adjacent to a prosthesis depends on stent composition, inductionof thermal apoptosis by ultrasound may prove to be effective in limitingrestenosis in polymeric stents and grafts. Issues that need to beaddressed include the optimal biocompatible material and design ofstents and the in vivo effects of phased-array US on the stented arteryand its surrounding tissues. Lal, et al. believed that by usingfast-heating, non-toxic materials, ultrasound-heated stents could bedevised.

Similarly, microwave radiation may be used to generate shape memoryeffects in shape memory alloys. It is known, for example, that microwaveradiation may be used for stent diathermy in stainless steel stents. S.Naguib, et al. in Stent diathermy using focused ultrasound & microwavefound at URL http://www.hotplaque.com/frames/abstracts/rabs3.htm soughtto use ultrasound and microwave energy to non-invasively heat the stentand its surrounding plaque. Using Palmaz-Schatz stents as well asseveral stent-shape biopolymer materials embedded inside the phantom,Naguib, et al. continuously mapped rise in temperatures in the systemupon ultrasound and microwave irradiations in separate settings.Temperature monitoring was done using a 12-channel ultra-thermometer(0.01° C.) with thermocouples (ultrasound) and fiber optic sensors(microwave). Therapeutic ultrasound at the frequency of 1-3 MHZ andintensity of 0.5-2.5 W/CM2 was used. Microwave radiofrequency wasdelivered by an antenna using a frequency of 2.45 GHZ and a power of5.37 & 10.22 watts. In their ultrasound experiment Naguib, et al. foundthat the temperature of outer surface of stent and its surroundingtissue increased significantly higher than other sites. The rise intemperature varies by the type of biopolymer where silicon stent heatedfaster and more than polyurethane and polytetrafluoroethylene. Similarresults were observed in the microwave experiments. Infraredthermography was used to measure the increased temperatures duringdelivery of both ultrasound and microwave radiation.

It is recognized, however, that externally applied forces, such as RF,microwave, ultrasound, etc. exist in the ambient environment. It is,therefore, undesirable to fabricate sensor device which will undergo ashape memory change upon encountering an ambient externally appliedforce. For example, it would be undesirable for a patient with animplanted sensor device responsive to microwave irradiation to have theimplanted sensor device undergo a shape memory transition when thepatient is warming food in a kitchen microwave appliance.

Because the microfabrication methods of the present invention allow forstringent control over the material composition of the implantablesensor device, the material composition may be made responsive to aparticular frequency range that is outside the frequency range of thesame type of energy signals existing in the ambient environment of thepatient. Thus, both the device activation energy type and frequency andthe detection energy type and frequency must fall outside thatencountered in the ambient environment.

It is well known that metal stents are radiopaque and are detectableunder radiographic imaging, such as fluoroscopy. Detection of theinventive sensor device may be accomplished by radiographic imaging,ultrasound imaging (either using frequencies which also generate a shapememory effect or not), magnetic resonance imaging, RF imaging or similarmethods. The use of magnetic resonance imaging to image nitinol stentsis known in the art. See, e.g., Randert, D, Hakim, B., MagneticResonance compatibility of Ni—Ti Stents, Abstract 8.P1, SMST-97conference (International Organization on Shape Memory and SuperelasticTechnologies) found at URLhttp://www.fwsystems.com/professional/smstabs.html, in which theydescribe they studied the compatibility of Ni—Ti coronary stents usingmagnetic imaging to assess a) ferromagnetic forces; and b) artifacts.Two methods were used to measure force: horizontal sliding and pendulumdeflection. Ferromagnetic forces were found to be less than 10% of stentweight. Artifacts were assessed to be small.

The use of particulate paramagnetic metal iron oxide as a contrastmedium to image and model vascular profiles under magnetic resonanceimaging (MM) has been demonstrated by Mitra Rajabi, et al. at theUniversity of Texas-Houston, Houston, Tex., United States and theUniversity of Texas-Medical Branch at Galveston, Galveston, Tex., UnitedStates. In an abstract published for presentation at the ACC 2001, theAmerican College of Cardiology Scientific Session scheduled for Mar.18-21, 2001, the abstract may be found at URL:http://www.hotplaque.com/ACC/ACC2001%20abstracts.htm#5), Rajabi, et al.describe a technique for imaging plaque inflammation. Super paramagneticiron oxide (SPIO) particles are magnetic resonance (MR) imaging contrastmedia that have a central core of iron oxide generally coated by apolysaccharide layer. They shorten the relaxation time, predominantlythe T₂ relaxation time. Rajabi, et al. hypothesized that inflamedvulnerable arteriosclerotic plaques would preferentially take up thesenano-particles by virtue of macrophage infiltration, leaking vasavasorum and fissured thin caps. To test their hypothesis, they injected1-3 mmol Fe/kg super paramagnetic iron oxide to six Apo E deficient andtwo C57bl mice through the tail vein, after first obtaining baseline MRimaging. Post-contrast MR imaging were performed in day 5 with the sameparameters (TR=2.5, TE=0.012, FOX=6 6, slice thickness=2.0 mm, flipangle (orient)=trans, and matrices=256×256). The aorta at the level ofkidney was selected for comparison of the baseline and post-contrastimages. Rajabi, et al. found decreased signal intensity in SPIO injectedApo E deficient mice and no decrease in signal intensity in SPIOinjected C57bl mice.

Thus, it is known in the art that thermal energy may be imparted toimplanted medical devices fabricated of metal either by transcatheterapproaches using direct application of heat, such as by a lasercatheter, or may be induced by directing microwave or ultrasound energytoward the implanted device. Moreover, it is known implanted medicaldevices fabricated of shape memory alloys may be detected in vivo usingradiography, ultrasonography, MRI, or RF imaging or combinationsthereof.

In accordance with the present invention, any of the foregoing methodsof applying energy to the inventive sensor device, either directlythrough transcatheter application or indirectly through inductivemethods, as well as any of the foregoing methods for detecting the stateof the inventive sensor device in vivo may be employed to effectuatechange in the state of the implanted device. The energy stimulus may bean endogenous energy stimulus selected from the group consisting offluid pressure, fluid shear forces, body temperature, cellular bindingor molecular binding. Alternatively, the energy stimulus may be anexogenous energy stimulus such as externally applied temperature,pressure, microwave, ultrasound, RF, ultraviolet, infrared, magneticresonance, x-rays, beta or gamma irradiation.

Turning now the accompanying Figures, and in particular FIGS. 1-4 thereis illustrated first and second embodiments of implantable in vivosensor in accordance with the present invention.

Temperature Sensor

The inventive in vivo temperature sensor 10 consists generally of animplantable tubular member 12 having a central lumen 14, an abluminalwall surface 16, a luminal wall surface 18 and at least one of aplurality of sensor regions 20 integral with at least one of theabluminal wall surface 16 and the luminal wall surface 18 of theimplantable tubular member 12. The flow vector F of a fluid over thesurface of the sensor region 20 is illustrated in FIG. 3. Each of the atleast one of a plurality of sensor regions further comprise a pluralityof cantilever members 22 patterned in an array on the implantabletubular member 12. The implantable tubular member 12, the sensor 20 andthe plurality of cantilever members may be fabricated of like materials,such as shape memory materials, or may be fabricated of differentmaterials, e.g., the implantable tubular member 12 being fabricated ofstainless steel and the sensor 20 and cantilever members 22 beingfabricated of a shape memory material, such as nickel-titanium alloys.In accordance with the best mode contemplated for the present invention,the tubular member 12, the sensor 20 and the cantilever members will befabricated of shape memory materials, such as nickel-titanium alloys.Where each of the plurality of cantilever members 22 are fabricated of ashape memory material, either individual cantilever members 22 or groupsof cantilever members 22 within a single sensor 20 may be fabricated tohave different martensite transition temperatures. Thus, for example,cantilever members 22 a within sensor 20 may be fabricated to have atransition temperature of X degrees Centigrade, while cantilever members22 b are fabricated to have a transition temperature of X+1 degreesCentigrade, cantilever members 22 c are fabricated to have a transitiontemperature of X+2 degrees Centigrade, etc. Alternatively all of thecantilever members 22 in a sensor 20 may have the same transitiontemperature, and a plurality of sensors 20 are provided such that sensor20 a has cantilever members having a transition temperature of X degreesCentigrade, while the plurality of cantilever members 22 in sensor 20 bare fabricated to have a transition temperature of X+1 degreesCentigrade, and the plurality of cantilever members 22 in sensor 20 care fabricated to have a transition temperature of X+2 degreesCentigrade, etc.

Each of the plurality of cantilever members 22 may be fabricated of amaterial capable of undergoing elastic, plastic, shape memory and/or asuperelastic deformation. Materials such as stainless steel, titanium,nickel, tantalum, gold, vanadium, nickel-titanium, or alloys thereof maybe employed to fabricate the plurality of cantilever members. Differentelectrical, thermal or mechanical properties may be imparted to thecantilever members 22 by altering the alloy ratios of the material. Itis preferable to vacuum deposit both the tubular member 12, the sensors20 and the cantilever members 22 to permit tight control over thematerial composition, electrical, mechanical and thermal properties ofthe material, as well as provide for tight control over the tissue andfluid contacting surfaces and the bulk material of the device. Forexample with nickel-titanium alloys, the titanium content of the target,in a nickel-titanium binary target, may be changed a known amount toprecisely alter the transition temperature of a cantilever members.

Each of the plurality of cantilever members 22 preferably have binaryfunctionality to provide a first “off” position indicative of anaustenite phase of the cantilever members 22 and a second “on” positionindicative of a martensite phase of the cantilever members 22. The first“off” position may be configured such that it is in a raised positionwhich projects outwardly relative to the sensor 20 and/or the tubularmember or in the lowered position that is substantially co-planar withthe sensor 20 and/or the tubular member 12. Similarly, the second “on”position may be configured such that it is in a lowered position that issubstantially coplanar with the sensor 20 and/or the tubular member 12or the cantilever members 22 may be in the raised position or projectingoutwardly relative to the sensor 20 and the tubular member 12, provided,however, that the first “on” position and the second “off” positions aredifferent from one and other.

It will be understood, therefore, that as the implanted temperaturesensor encounters different in vivo temperatures, different sets ofcantilever members will be exposed to their transition temperature andchange from the “off” position to the “on” position. In order to detectwhich cantilever members are in the “on” position and, therefore,determine the in vivo thermal conditions, the temperature sensor may beimaged radiographically, ultrasonically, magnetically or may be exposedto an external energy source which returns a signal representative ofthe number and position of the cantilever members that are in the “on”position. The returned signal may be generated by a passive transmitterembedded in solid state circuitry defined within the sensor 20, whereinthe cantilever members 20 serve as electromechanical switches whichalter a property of the solid state circuitry, for example, impedance orcapacitance, and which then returns a detectable signal representativeof the number and position of cantilever members 22 in the “on”position.

Pressure Sensor

Because it is structurally virtually identical to the temperature sensor10, described above, the inventive in vivo pressure sensor will also bedescribed with reference to FIGS. 1-4 and use identical referencenumerals to describe the elements thereof. The inventive in vivopressure sensor 10 consists generally of an implantable tubular member12 having a central lumen 14, an abluminal wall surface 16, a luminalwall surface 18 and at least one of a plurality of sensor regions 20integral with at least one of the abluminal wall surface 16 and theluminal wall surface 18 of the implantable tubular member 12. Each ofthe at least one of a plurality of sensor regions further comprise aplurality of cantilever members 22 patterned in an array on theimplantable tubular member 12. The implantable tubular member 12, thesensor 20 and the plurality of cantilever members may be fabricated oflike materials, such as superelastic materials, or may be fabricated ofdifferent materials, e.g., the implantable tubular member 12 beingfabricated of stainless steel and the sensor 20 and cantilever members22 being fabricated of a superelastic material, such as nickel-titaniumalloys. In accordance with the best mode contemplated for the presentinvention, the tubular member 12, the sensor 20 and the cantilevermembers will be fabricated of superelastic materials, such asnickel-titanium alloys. Where each of the plurality of cantilevermembers 22 are fabricated of a superelastic material, either individualcantilever members 22 or groups of cantilever members 22 within a singlesensor 20 may be fabricated to have different martensite transitiontemperatures. Thus, for example, cantilever members 22 a within sensor20 may be fabricated to have a martensitic stress/strain transitioncoefficient σ, while cantilever members 22 b are fabricated to have atransition coefficient σ+1, cantilever members 22 c are fabricated tohave a transition coefficient of σ+2, etc. such that differentcantilever members 22 or groups of cantilever members 22 change theirposition based upon a given quantum of stress or strain applied to thecantilever members 22 in vivo. Alternatively all of the cantilevermembers 22 in a sensor 20 may have the same transition temperature, anda plurality of sensors 20 are provided such that sensor 20 a hascantilever members having a transition coefficient σ, while theplurality of cantilever members 22 in sensor 20 b are fabricated to havea transition coefficient of σ+1, and the plurality of cantilever members22 in sensor 20 c are fabricated to have a transition coefficient ofσ+2, etc. such that different sensors 20 a, 20 b, 20 c respond todifferent stress-strain conditions.

Each of the plurality of cantilever members 22 may be fabricated of ashape memory and/or a superelastic material. Different electrical,thermal or mechanical properties may be imparted to the cantilevermembers 22 by altering the alloy ratios of the material. It ispreferable to vacuum deposit both the tubular member 12, the sensors 20and the cantilever members 22 to permit tight control over the materialcomposition, electrical, mechanical and thermal properties of thematerial, as well as provide for tight control over the tissue and fluidcontacting surfaces and the bulk material of the device. For example,with nickel-titanium alloys, the titanium content of the target, in anickel-titanium binary target, may be changed a known amount toprecisely alter the transition temperature of a cantilever members.

Each of the plurality of cantilever members 22 may have binaryfunctionality to provide a first “off” position indicative of anaustenite phase of the cantilever members 22 and a second “on” positionindicative of a martensite phase of the cantilever members 22. The first“off” position may be configured such that it is in a raised positionwhich projects outwardly relative to the sensor 20 and/or the tubularmember or in the lowered position that is substantially co-planar withthe sensor 20 and/or the tubular member 12. Similarly, the second “on”position may be configured such that it is in a lowered position that issubstantially coplanar with the sensor 20 and/or the tubular member 12or the cantilever members 22 may be in the raised position or projectingoutwardly relative to the sensor 20 and the tubular member 12, provided,however, that the first “on” position and the second “off” positions aredifferent from one and other.

Alternatively, rather than having merely binary functionality, each ofthe plurality of cantilever members 22 may have a response curve whichis dependent upon the modulus of the material and the moment of inertiaof each cantilever member. Each of the cantilever members 22 may beconfigured to have a variation in Z-axis thickness along an X-Y axis ofthe cantilever member 22. By configuring the cantilever members 22 withvariable Z-axis thicknesses, different cantilever members 22 ordifferent groupings of cantilever members will exhibit differentstress-strain responses due to the different material modulus anddifferent moment of inertia attendant to the altered geometry of thecantilever member 22. With this alternate construct of the cantilevermembers 22, for a given quantum of stress-strain applied to thecantilever members 22, the cantilever members 22 will deflect and shifta returned resonance frequency applied from an external energy source.The degree of deflection will then correlate to the stress and strainforces acting upon the cantilever members 22. It will be understood, ofcourse, that this alternate construct of the cantilever members 22 stillprovides binary “on” and “off” functionality with the “on” and “off”positions merely being indicative of the outlying positions of thecantilever member 22.

It will be understood, therefore, that as the implanted pressure sensorencounters different stress and strain associated with, for example,changes in physiological blood pressure, fluid shear stress,endothelialization, arterioschlerotic plaque development, different setsof cantilever members will be exposed to their transition conditions andchange from the “off” position to the “on” position. In order to detectwhich cantilever members are in the “on” position and, therefore,determine the stress-strain conditions, the pressure sensor may beimaged radiographically, ultrasonically, magnetically or may be exposedto an external energy source which returns a signal representative ofthe number and position of the cantilever members that are in the “on”position. The returned signal may be generated by a passive transmitterembedded in solid state circuitry defined within the sensor 20, whereinthe cantilever members 20 serve as electromechanical switches whichalter a property of the solid state circuitry, for example, impedance orcapacitance, and which then returns a detectable signal representativeof the number and position of cantilever members 22 in the “on”position.

With both the temperature sensor and pressure sensor embodiments, thecantilever members 22 may also be insulated from either the implantabletubular member 12 or from the sensor region 20. Thermal or electricalinsulators may be positioned intermediate the sensor region 20 and theimplantable tubular member 12 to insulate the implantable tubular member12 from heat or electrical transfer from the cantilever members 22 tothe implantable tubular member 12.

Vascular Imaging Sensor

We turn now to FIGS. 5-7B, in which there is illustrated the inventivein vivo sensor device 30 in the form of an endoluminal stent adapted fornon-invasive vascular modeling and imaging. The inventive in vivo sensordevice 30 comprises a plurality of structural elements 32, 36 that serveto define walls of the sensor device 30. The particular geometry of theplurality of structural elements 32, 36 may be selected based upon theintended function of the sensor device 30, e.g., a stent or stent-graft,and is not a significant factor in the present invention. It will beappreciated by those of ordinary skill in the art that alternativegeometries of the structural elements 32, 36 other than those depictedin the Figures are contemplated by the present invention. The pluralityof structural elements 32, 36 which define the sensor device 30 arefabricated of at least one of a shape memory materials, superelasticmaterials, plastically deformable materials and/or elasticallydeformable materials, such as stainless steel and/or nickel-titaniumalloys, that permit the sensor device 30 to expand within an anatomicalpassageway, for example a blood vessel, at body temperature, i.e., themartensite transition temperature (in the case of a shape memorymaterial) is below, but in proximity to, body temperature. In order toprovide sensor functionality and permit vascular imaging and modeling,the inventive sensor 30 further comprises regions of the structuralelements 32, 36 which have a second shape memory and/or superelasticmaterial therewith (hereinafter the “second material”), which has, forexample, a martensite transition temperature (or σ coefficient) which ishigher than that of the base material for the structural elements 32,36. Having a second material with either a higher transition temperatureor a higher σ coefficient, allows for changing device 30 geometry orconformation upon application of internally or externally appliedforces. For example, heat energy may be applied by either externalmicrowave transmissions directed from outside the body to the device 30or by a laser catheter that is used to apply laser energy to the sensordevice 30. In either case, localized heating of the sensor device 30 toabove the transition temperature of the second material causes thestructural elements 32, 36 to undergo martensitic transformation with aconcomitant change to the geometry and/or conformation of the sensordevice 30. Upon martensitic transformation, at least some of thestructural elements 32, 36 will change their positioning relative to thegeometry of the sensor 30, as represented by arrows 38 in FIG. 6,thereby changing the configuration of openings 37 between adjacent pairsof structural elements 32, 36. The sensor 30 in its changed geometryand/or conformation may then be imaged using conventional non-invasiveimaging techniques to provide an image of the vascular profile.

After retrieving a diagnostic image of the vascular profile, it may benecessary to remodel either the geometry or conformation of the sensordevice 30. For example, the device 30 may require elongation ordiametric enlargement (as depicted in FIGS. 7A and 7B). In order toremodel the sensor device 30, a superelastic material may be included insome of the structural elements 32, 36 which is responsive to externallyapplied forces, e.g., ultrasound, irradiation, microwave, ultrasound,RF, ultraviolet, infrared, magnetic resonance, x-rays and gammairradiation, which will alter the stress-strain applied to the sensordevice 30, causing a martensitic transformation in those portions of thestructural elements 32, 36 and a concomitant change in the conformationof device 30.

Additionally, because thermal changes in the sensor device 30 may beinduced by externally applied force, it is possible to both thermallyheat, and thermally cool the sensor device 30. Ex vivo cooling may beaccomplished by dampening the molecular vibrations induced by anexternal energy source, such as by shifting the frequency of theexcitatory signal by 180 degrees. By dampening the molecular vibrations,a cooling effect may be generated in the sensor device 30 in order toinduce localized cooling in the region of the sensor device 30.

Endoluminal Sensor

Also with reference to FIGS. 4-7B there is illustrated a sensor device30 which comprises a generally tubular member having a plurality of wallelements 32, 36 that define walls of the sensor device 30. The pluralityof wall elements are preferably fabricated of shape memory orsuperelastic materials such that the endoluminal sensor device 30effectively has at least two martensite transition points. Conventionalshape memory and superelastic materials have a single martensitetransition point. However, by fabricating all of the wall elements 32,36 of laminates of shape memory or superelastic materials such that oneply has a martensite transition point of T₁ and a second ply has amartensite transition point of T₂ wherein T₂>T₁, the first ply willcause the sensor device 30 to transition at T₁ which corresponds to thecondition for normal in vivo physiological conditions, while the anadditional quantum of energy, such as externally applied microwave,ultrasound, RF energy or internally applied energy, such as laserirradiation or direct thermal contact, will induce the conditionsuitable for transition at T₂ and the device will undergo a second shapetransition. Alternatively, portions of the wall elements 32, 36 may befabricated of a first material having a transition point T₁, while otherportions of the wall elements 32, 36, which are preferablynon-structural for the sensor device 30 under the T₁ conditions, but arestructural for the sensor device 30 under T₂ conditions, are fabricatedof a second material having a transition point T₂. Thus, those wallelements 32, 36 fabricate of the T₁ material will cause the sensordevice 30 to transition into an initial endoluminal shape or geometryunder the conditions appropriate to achieve transition point T₁, whilethose wall elements 32, 36 fabricated of the T₂ material will nottransition until the appropriate conditions for transition point T₂ areapplied to the sensor device 30.

Endothelialization BioSensor

Turning now to FIGS. 8-10 there is illustrated a biosensor 40 forsensing endothelialization events at the tissue-contacting surface ofthe sensor device. Like the inventive in vivo sensor devices describedabove, the inventive biosensor 40 consists generally of an implantablesubstrate carrier 42 having tissue contacting surfaces 42, 46 thereupon.For purposes of illustration only, biosensor 40 is depicted with theimplantable substrate carrier 42 being of a generally tubularconfiguration, such as for example, as stent. A plurality of bindingregions 50 are defined on either of the tissue contacting surfaces 42,46. The binding regions 50 are similar to the sensor regions of theabove-described embodiments, except the binding regions 50 compriseregions of the implantable substrate carrier 42 which have biochemicalmarkers, such as antibodies or ligands, bound thereto which are specificfor endothelial and/or smooth muscle cell surface proteins or precursorsof endothelial cell and smooth muscle cell proliferation, such asvascular endothelial growth factor or other growth factors. The materialof the implantable substrate carrier 42 is preferably fabricated of ashape memory or superelastic material, which, upon binding of biologicalmaterial to the biochemical markers in the binding regions 50, undergoesphase transformation due either the binding to the biochemical markersalone or in combination with an applied energy to the bound complex. Thephase transformation of the material of the implantable substratecarrier 42 will cause a frequency shift in a returned signal from theapplied energy source and will be indicative of the bound state of thebinding domains 50.

With particular reference to co-pending, commonly assigned U.S. PatentApplication Ser. No. 60/064,916, filed Nov. 7, 1997 which was publishedas PCT International Application WO9923977A1 entitled IntravascularStent And Method For Manufacturing An Intravascular Stent, both of whichare hereby incorporated by reference, the binding regions 50 may alsoform putative microgrooves 50 which are regions of the implantablesubstrate carrier 42 having patterned weakened atomic bonds in thecrystalline structure of the substrate carrier 42 material. Upon bindingof an endothelial cell, smooth muscle cell or a precursor thereof to thebinding domain, the material of the substrate carrier 42 may eitherdirectly undergo or be induced by an external energy source to undergo aphase transformation which will cause the weakened atomic lattice of thecrystalline structure of the substrate carrier 42 material to fractureand open a plurality of microgrooves 52 contiguous with the at thebinding regions 50. The microgrooves 52 may be propagated by theadditional binding of biological material to the markers at the bindingregions 50. In this manner, there are self-propagating microgrooveswhich facilitate endothelialization of the implanted substrate carrier.

While the invention has been described in connection with variousembodiments, it will be understood that the invention is capable offurther modifications. This application is intended to cover anyvariations, uses or adaptations of the invention following, in general,the principles of the invention, and including such departures from thepresent disclosure as, within the known and customary practice withinthe art to which the invention pertains.

What is claimed is:
 1. An implantable biosensor, comprising a tubularmember having a central lumen, an abluminal wall surface, a luminal wallsurface, the tubular member further comprising a plurality of struts, atleast one strut of the plurality of struts configured as a substratewherein at least one electronic circuit is integrated onto the substrateand into at least one of the abluminal wall surface or luminal wallsurface of the tubular member.
 2. The implantable biosensor of claim 1,wherein the tubular member is a stent.
 3. The implantable biosensor ofclaim 2, wherein at least some struts of the plurality of struts furtherinclude at least one recess in the abluminal wall surface of the atleast some struts of the plurality of struts.
 4. The implantablebiosensor of claim 3, wherein the at least one electronic circuit isintegrated within the at least one recess.
 5. The implantable biosensorof claim 4, wherein the at least one electronic circuit furthercomprises an integrated circuit or solid-state circuit.
 6. Theimplantable biosensor of claim 5, further comprising at least oneelectrode in electrical communication with the at least one electroniccircuit.
 7. The implantable biosensor of claim 5, wherein the at leastone electronic circuit is configured as at least one of an antenna, atransmitter, a power source and/or an electrode.
 8. The implantablebiosensor of claim 7, wherein the integrated circuit further comprisesan LC circuit.
 9. The implantable biosensor of claim 7, wherein thestent is an antenna operably coupled to the at least one electroniccircuit.
 10. The implantable biosensor of claim 5, wherein the at leastone electronic circuit is positioned within a width and depth of thegroove of at least one strut of the plurality of struts.
 11. A method ofmaking an implantable biosensor, comprising the steps of: a. Providing asubstrate for forming the implantable biosensor; b. Vacuum depositing adevice forming material onto the substrate; c. Masking portions of thedeposited device forming material to define grooves to be formed on thedevice forming material; d. Forming grooves in a surface of the deviceforming material; e. Depositing at least one electrical component layerof a plurality of electrical component layers into the groove; and f.Forming surface features on a surface of at least some of the electricalcomponent layers of the plurality of electrical component layers. 12.The method of claim 11, wherein step b further comprises the step ofdepositing a shape memory metal.
 13. The method of claim 12, furthercomprising the step of depositing an electrically conductive layercoupling at least one electrical component layer of the plurality ofelectrical component layers to the device forming material.
 14. Themethod of claim 13, further comprising the step of depositing anelectrically conductive layer coupling at least one electrical componentlayer of the plurality of electrical component layers to anotherelectrical component layer.
 15. An implantable biosensor, comprising atubular member having a central lumen, an abluminal wall surface, aluminal wall surface, the tubular member further comprising a pluralityof struts, at least one strut of the plurality of struts configured as asubstrate wherein at least one electronic circuit is integrally formedonto the substrate and into at least one of the abluminal wall surfaceor luminal wall surface of the tubular member.
 16. The implantablebiosensor of claim 15, wherein the tubular member is a stent.
 17. Theimplantable biosensor of claim 16, wherein at least some struts of theplurality of struts further include at least one recess in the abluminalwall surface of the at least some struts of the plurality of struts. 18.The implantable biosensor of claim 17, wherein the at least oneelectronic circuit is integrally formed within the at least one recess.19. The implantable biosensor of claim 18, wherein the at least oneelectronic circuit further comprises an integrated circuit orsolid-state circuit.
 20. The implantable biosensor of claim 19, furthercomprising at least one electrode in electrical communication with theat least one electronic circuit.